The objectives are: 1) to advance our understanding of the cytochrome c oxidase reaction with O2 in vivo using non-invasive optical monitoring techniques; 2) to describe in detail the interrelations between physiological function and the regional oxidative metabolism required to underwrite the work; and 3) to do so, using patients with pulmonary and/or cardiovascular compromise jeopardizing O2 delivery to peripheral tissue such as brain and muscle. There are three specific aims. We will ascertain in detail the correlation between the cerebral redox steady states of the copper moiety of cytochrome c oxidase under various hypoxic challenges and the better known heme a responses. Challenges will be primarily in the form of hypoxic and CO-induced hypoxia of varying severity. We will correlate, in a few hypoxic states, the redox signals with biochemical profiles obtained by freeze-trapping and subsequent biochemical analysis. We will determine the limits of the oxidative metabolic system to respond in the normal, oxidizing fashion to the imposed, additional load incurred by direct stimulation of the cerebral cortex. We will stimulate the cortex directly and record both the electrical response and the Transient Metabolic Response (TMR) of cytochrome c oxidase in terms of polarity, extent and kinetics. Once the limits of the oxidative response (the so-called Threshold for Functional Activity, TFA) have been ascertained over a wide range of hypoxic and induced activity levels, a separate, limited study will combine optical monitoring with freeze-trapping and analysis. In another brief series the TMR will also be measured in skeletal muscle in preparation of the 4th specific aim below. We will correlate selected features of the peripherally evoked potential with the redox state at different degrees of hypoxia. The same type of kinetic analysis as proposed for direct cortical stimulation will be attempted. In year 03 we will initiate work on combined optical redox monitoring and determination of cerebral O2 uptake (CMRO2) and VO2 of skeletal muscle. Upon successful completion of these tasks the primary forcing function will then be changed from pure hypoxia to hypoxia complicated by respiratory and metabolic acidosis and alkalosis, hypotension and hemodilution.